Production of unsaturated carbocyclic ketones

ABSTRACT

Preparation of Alpha , Beta -unsaturated carbocyclic ketones by reacting an enol lactone with a carbanion generated by treatment of a methylphosphonate or a mono-substituted methylphosphonate with base.

United States-Patent [191 Fried [111 8 3,855,247 I451 Dec. 17, 1974 [541 PRODUCTION OF UNSATURATED CARBOCYCLIC KETONES [21] Appl. No.: 198,476

Related U.S. Application Data [60] Division of Ser. No. 773,320, Nov. 4, 1968, Pat. No. 3,652,596,. ivhich is a continuation-in-part of Ser. NOS. 747,465, July 25, I968, and Ser. N0. 687,502, Dec. 4, 1967, Pat. No. 3,639,428.

[52] U.S. Cl 260/340.9, 260/338, 260/340.7, 260/345.9, 260/347.8, 260/476 C, 260/488 B, 260/586 H [51] Int. Cl C07d 13/08 [58] Field of Search..... 260/340.9, 586 H, 345.9, 260/488 B, 338 R, 340.7, 347.8

[56] References Cited UNITED STATES PATENTS 2,744,122 5/1956 Djcrassi 260/397.4

3,150,152 9/1966 Joly 260/326.5 3,309,383 3/1967 Pappo 260/343.3 3,050,550. 8/1962 Nomin et a1. 260/476 3,019,252 1/1962 Nomin et alt. 260/476 2,754,319 7/1956 .10hnston.... 260/461 3.317.565 5/1967 Seeger 260/345.8 3,318,922 5/1967 Windholz et a1... 260/397.4

3,102,145 8/1963 Nomin et a1. 260/586 3,057,907 10/1962 Farinacci 260/468.5

3,413,314 11/1968 Amiard et a1 260/343.2 3.652.596 3/19-72 Fried 260/340.9

3,639,428 2/1972 Fried 260/345.9 2,846,446 8/1958 Know1es..... 260/340.5 3,321,489 5/1967 Los 260/343.2

FOREIGN PATENTS OR APPLICATIONS 6.707.919 12/1967 Netherlands 260/476 6,414,702 6/1965 Netherlands 260/476 1,480,247 4/1967 France 260/345.9 801,276 12/1950 Germany 260/345.9 629,251 10/1963 Belgium 260/345.9 1,496,817 8/1967 France 260/345.9 1,359,675 12/1964 France.... 260/345.8 1,465,400 12/1966 France 260/345.8

OTHER PUBLICATIONS Velluz-et a1., Tetrahedron, Suppl. 8, part 11, pp. 495-505 (1966). QD241.T4

Simpson et al., Tetrahedron Letters, No. 33, pp.'

3209-3211, 1967, Pergamon Press, Ltd. (Gt. Britain). QD24I.T42

Stork et a1., JACS, 82, No. 21, 5464 (1967).

Hughes et a1., Chemistry and Industry, (London), 1022 (1960). TP1.S63

Burger et a1., Medicinal Chemistry, 2nd. ed., Interscience, London, 1960, p. 42. RS403.B8

Snyder et al., J.A.C.S. 72: 2965-2967 (1950). Synthetic Methods of Organic Chemistry, Theilheimer, ed. article by Walker, Vol. 13, pt. 862, page 414 (1958).

Heard et a1., Synthetic Methods of Organic Chemis-v try, Vol. 8, p. 354-355, para. 884, (1954). QD.262.T4 I

Primary Examiner-Richard J. Gallagher Assistant ExaminerRa1ph-McCloud Attorney, Agent, or Firm-Lawrence S. Squires; William B. Walker I [57] ABSTRACT Preparation of a,B-unsaturated carbocyclic ketones by reacting an enol lactone with a carbanion generated by treatment of a methylphosphonate or a monosubstituted methylphosphonate with base.

10 Claims, No Drawings PRODUCTION OF UNSATURATED CARBOCYCLIC KETONES This is a division of application Ser. No. 773,320 filed used herein, refers to a carbocyclic ketone having a,B-ethylenic unsaturation in respect to the keto group.

Prior to the present invention, enol lactones were converted into afi-unsaturated carbocyclic ketones by a two-step process which involved reacting the enol lactone with about one equivalent of a Grignard reagent, for example,methyl-magnesium chloride, to open the lactone ring and thereafter the thus-obtained diketonic intermediate product was cyclized by treatment with acid or alkali to obtain the carbocyclic ketone. See, for example, US. Pat. Nos. 3,057,907 and 3,321,489 and French Pat. No. 1,359,675. In addition to the disadvantage that the conversion of enol lactones into carbocyclic ketones requires at least two steps, prior methods are often difficult to control, unsuitable for -membered ring systems, and of very narrow utility in that the afi-unsaturated carbocyclic ketones obtainable are very limited.

A primary object of the present invention, therefore, is to provide a process for the production of a,B-unsaturated carbocyclic ketones from enol lactones which overcomes the aforementioned disadvantages. Another object of the present invention is to provide a process for the production of a,B- unsaturated carbocyclic ketones which is economical and simple to operate but yet of great flexibility or adaptability in respect to the type of a,B-unsaturated carbocyclic ketone that can be produced. Another object of this invention is to pro-.

vide a single-step process for the production of a,B-unsaturated carbocyclic ketones. Still another object of the present invention is to provide a process forthe production of B-unsaturated carbocyclic ketones which is useful in the total synthesis of steroids and to novel intermediatestherefore. Other objects, advantage and meritorious features of the present invention will become apparent as the invention is described in more detail hereinafter.

In accordance with the foregoing objects of the present invention, there has been discovered a' very versa-'- tile process for theproduction of 0:,{3-unsaturated carbenzoyl-7,8-dimethoxyisocoumarin, expression a,B-unsaturated carbocyclic ketone, as 7 carbocyclic ketones in general. The enol lactone can be either a monocyclic enol lactone or a polycyclic compound such as bicyclic, tricyclic and tetracyclic enol lactones depending upon the B-unsaturated carbocyclic ketone desired to be obtained. The process of the present invention is particularly suitable for enol lactone starting materials wherein the heterocyclic ring thereof contains at least 5 members and monoethylenic unsaturation. The enol lactones which can be converted into a,B-unsaturated carbocyclic ketones by the process of this invention are too numerous to list.

Exemplary of the monocyclic and polycyclic enol lactones which can be used in the process of the present invention are a,a,y-trimethylbut-2-enolide, A -valeryl lactone, isocoumarin, 3-methyl-6,8- dimethoxyisocoumarin, 3-phenylisocoumarin, 3- 3- chloroisocoumarin, benzal phthalide, 5,6,7- trimethoxyisocoumarin, 8-lactone of lB-hydroxy-ZB- methyl-2a-(2-carboxyethyl)-3-hydroxycyclopent- 3-ene, 8-lactone of 1B-hydroxy-4- (2-carboxyethyl)-5- hydroxy-7aB inethyl-3ad;4B,7,7a-tetrahydroindane,

4-oxa-17B-acetoxyandrost-5-en 3-one, 3-ethoxy-17- oxa-D-homoestral ,3,5( 10), l5-tetraen- 1 7-one, 4-oxacholest-5-en-3-one, l7, 20;20,2 1-

o RJ-CHz-L on),

wherein R is selected from the groupconsisting of substituted and unsubstituted, saturated and unsaturated, aliphatic carbocyclic and carbocyclic-aliphatic radicals and R is selected from the group consisting of substituted, and unsubstituted, saturated and unsaturated, aliphatic, carbocyclic and carbocyclic-aliphatic radicals.

Phosphonates of formulas A and B above can be prepared, forexample, by the reaction of a di-substituted phosphite (C) with an organic halide or sulfonate of the formula D and E, respectively, in the presence of a base, e.g., sodium hydride, 1 i

I n -cm-x cH -x and 3-methoxy-l6-oxaestra-1,3,5( l0),8, l-4- In the above formulas, 'R and R'v are as defined above and X is chloro or bromo or OSO- R, wherein R, is alkyl or aryl. The formation of the pphosphonates can be carried out in inert solvents such as ether, tetrahydrofuran, monoglyme, diglyme, or dioxane andpreferably in an oxygen-free atmosphere. The method of preparing the phosphonates is not part of the present invention. A suitable procedure for the formation of methylphosphonates and mono-substituted methylphosphates useful in the present invention is to react a disubstituted phosphite of formula C with an organic halide or sulfonate of formulas D and E in an inert solvent in the presence of about one equivalent of a base such as sodium hydride under an inert atmosphere at a temperature of about --lOC to about room temperature. Other methods are described in, for example, US. Pat. No. 2,754,3 l9. While the methylphosphonates and mono-substituted methylphosphonates which can be employed in the process of the present invention are too numerous to list here, they can be exemplified by the following:

dimethyl methylphosphonate dimethyl ethylphosphonate diethyl benzylphosphonate diethyl methylphosphonate dicyclohexyl methylphosphonate diphenyl methylphosphonate di-(n-butyl) methylphosphonate dibenzyl methylphosphonate diethyl methylphosphonate diethyl 4,4-dimethoxybutylphosphonate diethyl 4,4-ethylenedioxypentylphosphonate diethyl 4,4-dimethoxy-3- methylbutZ-enylphosphonate diethyl 4-chloropent-3enylphosphonate diethyl 4-(tetrahydropyran-2'-yloxy)-pentylphosphonate diethyl 4,4-ethylenedioxy-3methylpentylphosrjhonate di(methoxyethyl) methylphosphonate di(Z-ethylhexyl) methylphosphonate di(n-octyl) ethylphosphonate di(ethoxyethyl) methylphosphonate In the practice of the process of the present invention, a phosphonate of formula A or B is reacted with a base to generate the corresponding carbanion of the formulas A and B, respectively:

. R -03k (OR):

o CHr-l (03): w

, of the reaction mixture is maintained during the addition of the enol lactone and thereafter the cooling means removed or otherwise raising the reaction temperature to about room temperature. Suitable bases for generating the carbanion include organo alkali metal compounds such as n-butyl lithium, phenyl, lithium, methyl sodium, sodium acetylide, methyl potassium,

methyl lithium, tolyl lithium, methyl potassium lithium pyridide, and the like; alkali metal hydrides such as sodium hydride, potassium or lithium hydride; alkali metal amides such as sodamide, and the like.

in practicing the conversion of an enol lactone into the corresponding 0:,B-unsaturated carbocyclic ketonc in accordance with the process of the present invention, the reaction is carried out using about equal molar amounts of the phosphonate, base and enol lactone. More than one molar equivalent of the phosphonate and base can be used but it is generally disadvantageous to do so because the excess reagent may react further with the carbonyl group of the desired carbocyclic ketone. Thus, it is preferred to use about one molar equivalent of the phosphonate and base or a modest excess of each such as up to about 1.2 molar equivalents. Any organic solvent can be used for the reaction medium so long as it is inert to the reaction and liquid at the reaction temperature being used. Suitable organic solvents include ether, tetrahydrofuran, dioxane, monoglyme, diglyme, and the like. The reaction between the carbanion and enol lactone generally goes to completion in from about 0.5 hours to about 48 hours depending upon such factors as temperature and the relative reactivity of the carbanion and the enol lactone. The reaction temperature can vary from about l50 C to about room temperature, preferably about l00C to about room temperature depending upon such'factors as the stability of the carbanion, the relative reactivity of carbanion and enol lactone being reacted and the time in which it is desired to complete the reaction. After formation of the carbanion is complete and the enol lactone has been introduced, the reaction mixture can be permitted to rise to about room temperature in order to complete the reaction in a shorter period of time. Depending upon the-stability of the particular carbanion being used, the reaction mixture can be heated above room temperature, for example, reflux temperature, if still shorter reaction times are desired. However, because of the general instability of the carbanion, the reaction between the phosphonate and base must be carriedout at low temperatures of the order of about l50C to 20C.

There is formed an intermediate phosphonate which in some cases can also be isolated, if desired, or the reaction continued without interruption to form the afi-unsaturated carbocyclic ketone. As shown more fully hereinafter, whether an intermediate phosphonate is formed that can be isolated is dependent upon the reactivity of the particular phosphonate carbanion and enol lactone being reacted, the solvent medium and the reaction temperature. If it is desired to isolate the intermediate phosphonate, it should generally be done before permitting the reaction to rise to warm temperature such as about 0C or lower by, for example, the addition of water followed by extraction with organic solvent such as ether, ethyl acetate, and the like. If it is not desired to isolate the intermediate phosphonate, the reaction can be continued without interruption or it can be continued more efficiently by the addition of a lower monohydric aliphatic alcohol such as methanol, ethanol, isopropanol, t-butanol, and the like, with or without the addition of a base such as an alkali metal alkoxide or hydroxide, for example, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, potassium methoxide, sodium t-butoxide, and the like. The lower alcohol or an alcohol containing a base cent by volume of the total amount of solvent in the reaction mixture, preferably from about 25 to 80 percent. When the intermediate phosphonate is isolated, the amount of base added should generally be at least 1 molar equivalent. The most advantageous amount of base is easily determinable by routine experimentation giving consideration to the enol lactone, phosphonate and solvent being employed. In the case of solvents such as diglyme and monoglyme, if it is not desired to isolate the intermediate phosphonate, it has been found advantageous to add, after the initial reaction, from about 10 to 75 percent preferably to 50 percent, by volume of the total solvent, a dipolar aprotic solvent such as hexamethylphosphora'mide', dimethylformamide, dimethylacetamide, and the like. A particularly preferred reaction solvent is diglyme. In the foregoing methods, when it is not desired to isolate the intermediate phosphonate, the efficiency of the reaction is generally increased by increasing the reaction temperature, after the initial reaction, to above room temperature, such as reflux temperature. For optimum results, it is important that the reaction be conducted under as near anhydrous conditions as possible and preferably under an inert oxygen-free atmosphere such as nitrogen; argon, and the like. While the concentration of the enol lactone and carbanion doesnot appear to be critical, it is preferred to operate at low concentrations .of the order of about 2 to about .25 percent by weight of the reaction medium.'The foregoing reaction conditions are largely dependent upon the particular phosphonate, base and enol lactone employed and are presented as a guide. Provided with the foregoing and the examples hereinafter, the most advantageous or optimum conditions and proportions of the enol lactone, phosphonate and base for a particular a,B-unsaturated carbocyclic ketone areeasily determinable by one of ordinary skill in the art using routine experimentation.

In the case of enol lactone starting materials having other carbonyl groups present, e.g., an isolated keto group, it is preferable to introduce a prote'ctinggroup prior to the reaction. In general, the phosphonate anions tend to react faster with the enol lactone group. An isolated keto group can be protected as through formation of the corresponding lower alkylenedioxy or ketal such as ethylenedioxy or propylenedioxy and the keto group regenerated by treatment with acid following completion of the reaction of the enol lactone and phosphonate anion. Alternatively, an isolated keto group can be reduced to the free hydroxy by the use of reducing agents such as lithium aluminum hydride, lithium tri(t-butoxy)-aluminum hydride or sodium borohydride and subsequently oxidized using, e.g., chromium trioxide or Jones reagentfollowing-completion of the reaction. If a free hydroxyl group is present, there may be some reaction of the hydroxy group with the carbanion and hence require that an excess of the carbanion be used. It is preferred to protect hydroxyl groups by esterification to a carboxylic ester such as acetate. benzoate, cyclopentylpropionate, mesitoate, and the like, or by etherification. Since the ester group in some cases will reactwith the carbanion to some extent, it is preferred to convert free hydroxyls of thestarting material into an acid labile ether group such as tetrahydropyran- 2-yloxy, tetrahydrofuran-Z-yloxy, methoxy, ethoxy, or methoxymethylenoxy and especiallyt-butoxy. In general, however, the carbanion tends to react faster with the enol lactone groups.

Depending upon the particular enol lactone starting material, there is formed in some cases Lily-carbocyclic ketone along with the a,B-unsaturated carbocyclic ketone.

The term lower alkyl, as used herein, refers to a saturated aliphatic hydrocarbon group, branched or straight chain, containing one to six carbon atoms. The term monoaryl refers to phenyl and substituted phenyl such as tolyl, chlorophenyl, methoxyphenyl, and the like. Carboxylic acyl and carboxylic acyloxy refer to an acyl group and acyloxy group, respectively, containing less than 12 carbon atoms. Typical ester groups thus include a'cetate,-propionate, butyrate, benzoate, mesitoate, cyclopentylpropionate, enanthate, trimethylacetate, t-butylacetate, adamantoate, and the like.

The novel process of the present invention is particularly useful for the production of carbocyclic ketones admirably suited for the synthesis of steroids. One application of the process of the present invention is illustrated below in a novel route for the synthesis of l9-nor steroidswherein R is t-butyl and R is lower alkyl.

In the practice of the above process, the novel tricarbocyclic enol lactone (I') is reacted with the anion of 4-cycloethylenedioxypentylphosphonate of the -following formula:

in which R is as defined above to yield the a,B-unsaturated tricarbocyclic ketone (Il').

The a,B-unsaturated ketone U1) is. treated with aqueous organic acid such as acetic acid to yield the dione UN). The dione (llI) is subjected to catalytic hydrogenation using, e.g., palladium-on-carbon or barium sulfate to yield the saturated dione (IV'). The saturated dione is cyclized using either acid to afford l9-nortestosterone (Vl') or using base to yield the tbutyl ether of l9-nortestosterone (V). Cyclization with acid is accomplished with a mineral acid such as sulfuric acid or hydrochloric acid with concomitant removal of the t-butyl group. Suitable bases for ,cyclization include all-:ali hydroxides such as sodium hydroxide. The l9-nor steroids of formulas V and VI are useful anabolic agents and intermediates'for preparing other useful steroids such as l7a-ethynyl-l7B-hydroxyestr-4-en-3-one (U.S. Pat. No. 2,744,122) by oxidation followed by ethynylation.

The following examples are provided to illustrate the present invention. Temperature indegrees Centigrade.

EXAMPLE l R! .R I

l CHr-iKOR):

(III) in the above formulas, R and R are as defined above and R is 0x0 or the lower alkylenedioxy or ketal thereof or the group in which R is hydroxy or the carboxylic ester or labile ether-thereof;

To a solution of l g. of dimethyl methylphosphonate in 30 ml. of dry tetrahydrofuran under nitrogen and cooled to 78, there is added one equivalent of n-butyllithium in hexane with stirring. After about 10 minutes at 78, one equivalent of the tricyclic enol lactone l (R is methyl; R is in which R is benzoyloxy) in 35 ml. of dry tetrahydro-' .furan is added. The reaction mixture is allowed to rise in which R is benzoyloxy) which can be further purified by chromatography, if desired.

EXAMPLE 2 To a solution of 4 g. of diethyl 4-cycloethylenedioxypentylphosphonate V (R is ethyl) in 50 ml. of dry monoglyme under nitrogen and cooled to about 80, there is added one equivalent of n-butyl lithium in hexane with stirring. After about 5 minutes at 80, one equivalent of the tricyclic enol lactone I (R is methyl; R is in which R. is benzoyloxy) in ml. of dry monoglyme is added and the reaction mixture allowed to rise to room temperature. The reaction mixture is allowed to stand for about 2.5 hours and then diluted with water. The mixture is extracted with ether and the ether extracts combined, washed, dried and evaporated under reduced pressure to give the tricarbocyclic ketone Vl (R is methyl; R is in which R is benzoyloxy) which can be further purified by chromatography on alumina.

The mono-substituted methylphosphonate (V) can be prepared using the following procedure.

To a solution of 5.5 g. of pure sodium hydride in 200 ml. of dry tetrahydrofuran under nitrogen, there is added one equivalent of dry diethyl phosphite. The mixture is cooled in an ice-bath and stirred at 0 for 1.5 hours. One equivalent of the ethylene ketal of lbromopentan-4-one in 60 ml. of dry tetrahydrofuran is added and the mixture stirred for l5 minutes at 0 and allowed to stand 16 hours at room temperature. The mixture is then heated under reflux for three hours, cooled and filtered. The filtrate is concentrated under reduced pressure and the concentrate taken up in ether. This mixture is shaken with saturated aqueous sodium chloride and then separated. The organic layer is separated and concentrated under reduced pressure to give diethyl 4,4,-ethylenedioxypentylphosphonate (V) (R is ethyl) which is purified bydistillation in vacuo (b.p. 115 at 0.05 mm.).

B y using other phosphites, e.g., dimethyl phosphite, dibenzyl phosphite or diphenyl phosphite, in place of diethyl phosphite in the above procedure, the corresponding di-substituted phosphonates are obtained.

EXAMPLE 3 in which R" is benzoyloxy) in 50 ml. of dry tetrahydrofuran while maintaining the temperature at about 78.

The reactionmixture is allowed to warm to room temperature and to stand at room temperature for 3 hours. The reaction mixture is diluted with water and then extracted with ether. The'ether extracts are combined, washed, dried and evaporated under reduced pressure to give the bicarbocyclic ketone Vlll (R is methyl; R7

in which R is benzoyloxy) which can be further purified by chromatography or fractional distillation.

The a,/3-unsaturated bicarbocyclic ketones of formula VIII are useful intermediates for the synthesis of steriods using the method of, for example; Whitehurst et a1., U.S. Pat. No. 3,317,566.

The bicyclic enol lactones of formula VII can be prepared using the following typical procedure or the method of French Pat. No. 1,496,817 (1966).

A mixture of 0.3 g. of Z-methylcyclopentane-l,3- dione, 0.33 ml. of methylacrylate and 0.1 g. of potassium t-butoxide in 200 ml. of t-butanol is allowed to stand at about 20C for 72 hours. The reaction mixture is washed with water, dilute sodium hydroxide and then water to neutral, dried and evaporated to give 2- methyl.-2-( ,B-carbomethoxyethyl )cyclopentane-l ,3- dione which is purified by distillation.

A mixture of 5 g. of the diketoester (VII(, ml. of tetrahydrofuran and 1,3molar equivalents of lithium tri-t-butoxyaluminum hydride is heated at reflux until the hydride reagent is consumed. The reaction mixture is cooled, diluted-with concentrated aqueous sodium sulfits solution and the resulting clear supernatant decanted and evaporated. The resulting residue is puri fied by chromatography on alumina to furnish 0.3 g. of

the following alcohol:

on Cg on,

which is converted into the corresponding benzoate by treatment with benzoyl chloride in pyridine. The methyl ester is hydrolyzed to the acid which is then cyclized to furnish the enol lactone of formula II wherein R is methyl and R is in which R is benzoyloxy. By using 2-ethylcyclopentane-1,3-dione and 2- propylcyclopentane-l,3-dione in place of 2- methylcyclopentane-l ,3-dione in the above procedure,

EXAMPLE '4 The process of Example 3 is repeated with the exception of using an equivalent amount of phosphonate of formula IX (R is ethyl; R is hydrogen; R is methyl in r 11 place of dimethyl methylphosphonate and the substituted bicarbocyclic ketones (X) are obtained.

In the above formulas, R, R and R are as defined hereinabove, R- is hydrogen or a lower alkoxy of one to six carbon atoms and R is lower alkyl.

By using other phosphonates of formula lX in the above process, the correspondingly substituted :,B-unsaturated bicarbocyclic ketones of formula X are obtained.

The phosphonates of formula IX can be obtained by using an equivalent amount of the bromide (XI) in place of the ethylene ketalof l-bromopentan-4-one in the procedure set out in Example 2. The bromide (XI) ,can be prepared from the corresponding acid by the following procedure.

Ten grams of m-methoxycinnamic acid in 100 ml. of ethanol is hydrogenated with 0.5 g. of pre-reduced l0 percent palladium-on-charcoal until the uptake of hydrogen ceases. The catalyst is removed by filtration and the filtrate evaporated to yield 3-(m-methoxyphenyl)- propionic acid.

A solution of g. of the foregoing propionic acid in l00- ml. of tetrahydrofuran is added cautiously to a boiling solution of 250 ml. of tetrahydrofuran containing 3 g. oflithium aluminum hydride. The reaction mixture is refluxed overnight with stirring and then cooled and the excess of hydride decomposed by the cautious addition of ethyl acetate and then saturated sodium sulfate. The resulting clear solution is decanted and dried over sodium sulfate. The solvent remaining is removed by distillation to give 3-(m-methoxyphenyl)propanol which is purified by distillation in vacuo. One gram of this propyl alcohol in 50 ml. of benzene is boiled with a slight excess of phosphorus tribromide until thin layer chromatography no longer indicates the presence of starting alcohol. The reaction mixture is cooled, washed with water and dilute sodium carbonate solution, dried over sodium sulfate and concentrated to dryness to give 3-(m-methoxyphenyl)propyl bromide (Xl) (R is hydrogen; R is methyl) which is purified by distillation,

By using 3,5-dimethoxycinnamic acid in place of mmethoxycinnamic acid, and bromide (XI) in which R is methoxy and R is methyl is obtained.

The bicarbocyclic ketones of formula X above can be converted into estra-l,3,5( lO),8,l4-pentanes by treatment with p-toluenesulfonic acid in benzene or by the method of U.S. Pat. No. 3,317,566.

EXAMPLE 5 To a suspension of 4 g. of dibutyl methylphosphonate in ml. of dry monoglyme at about --78 under nitrogen, there is added with stirring one equivalent of nbutyl lithium in hexane. After about 10 minutes, there is added one equivalent of l7B-acetoxy-4-oxa-androst- 5-en-3-one in 75 ml. of dry tetrahydrofuran whilemaintaining the temperature at about 78. The reaction mixture is allowed to warm to room temperature and thenleft to stand for about 4 hours. The reaction mixture is diluted with water and extracted with ether. The other extracts are combined, washed, dried and evaporated to give testosterone acetate (l7B-acetoxyandrost-4-en-3-one) which can be purified by chromatography.

By using diethyl ethylphosphonate in the process of this example, the corresponding substituted tetracarbocyclic compound is obtained, i.e. 4-methyl testosterone acetate.

By using other steriodal enol lactones in the above process in place of l7B-acetoxy-4-oxandrost-5-en- 3-one as the starting material, e.g., 4-oxacholest-5-en-' 3-one, 3-ethoxyl 7-oxa-D-homoestral ,3,5( 10),] 5- tetraenl 7-one, l7,20;20,2 l-bis-methylenedioxy-l l B- hydroxypregn5-en-3-one, and the like, the corresponding a-B-unsaturated tetracarbocyclic ketone is obtained, e.g., cholest-4-en-3-one, 3-ethoxy-D- homestra-l,3,5(l0), 14-pentaen-l7-one, and 17,20; 20,2l-bismethylenedioxy-l 1B-hydroxypregn-4-en-3- one EXAMPLE 6 trimethylcyclopent-Z-en-l-one (XlV) which can be pu-' rifie'd by vacuum distillation.

By using a mono-substituted methylphosphonate, for example, diethyl ethylphosphonate in the above process, the corresponding 2-substituted a,,B-unsaturated cyclopentone is obtained, e.g., 2,3,5,5- tetramethylcyclopent-2-en- 1 -one.

EXAMPLE 7 To a solution of 5 g. of dimethyl methylphosphonte in ml. of dry tetrahydrofuran cooled to about -7 8 under nitrogen, there is added with stirring one equivalent of n-butyl lithium in hexane. After about 10 minutes, there is added one molar equivalent of 3- methoxy-l 6-oxaestra-l ,3 ,5( l0),8, l 4-pentaenl 7-one in dry tetrahydrofuran while maintaining the temperature at about -78. The mixture is allowed to warm to room temperature and then left to stand at room temperature for 5 hours. The mixture is diluted with water and then extracted with ether. The ether extracts are combined and concentrated to furnish a residue which is chromatographed on neutral alumina eluting with benzene to afford 3-methoxy-l4B estra- 13 l,3,5( 10),}3, 1 S-pentaen- 1 7-one and 3-methoxyestral,3,5(I),8,l4-pentaen-l7-one which can be further purified by recrystallization from aqueous methanol.

0.5 g. of 3-Methoxyestra-l,3,5(l0),8,l4-pent aenl7one in 25 ml. of ethanol is reduced catalytically with 50 mg of 5 percent palladium-on-charcoal until a molar equivalent of hydrogen is taken up. The catalyst is filtered off and the filtrate evaporated to dryness to .yield the known 3-methoxyestra-l ,3,5 l0),8-tetraenl7-one which can be converted into estrone methyl ether by procedures outlined in Chemistry & Industry (London), l()22 (1960) or into l9-nor-A" steroids using the procedure of, forexample, U.S. Pat; No. 3,3l8,922.

By repeating the above process using other l6-oxa steroids of the formula XV, e.g., 3-methoxy-l5-methyllo-oxaestral ,3,5( l0),6,8, l 4-hexaen-l 7-one as the tetracyclic enol lactone starting material, the corresponding steroidal ketone t'etracarbocyclic ketone) of the formula XVI is obtained by e.g., 3-methoxy-l5- methylestra-l,3,5(l0),6,8,l4-hexaen-l7-one and 3- methoxy-l 5-methyl-l4Bestra-l ,3,5( l0),6,8, l 5 hexaen-l7one.

The tetracyclic enol lactones of formula XVcan be prepared according to the method of Simpson et al., Tetrahedron Letters, 3209 (1967) or U.S. Pat. No.

EXAMPLE 8 The process of Example 2 is repeated with the exception that the phosphonate employed is a phosphonate (XVII'I) and 0.5 moles of pip'eridine in benzene is'refluxed using a water separator until no more water distills from the reaction mixture. The reaction mixture is then cooled, washed and dried to afford the 4-piperidyl-lacetoxypent-3-ene (XIX). A-mixture of 5 g. of XIX in 100 ml. of. dioxane is treated with an excess of methyl iodide at 20C for 18 hours and then heated at 70C for 6 hours. The reaction mixture is concentrated to a small volume, diluted with water and l-acetoxy-3- methyIpentan-4-one isolated by extraction with ethyl acetate. A mixture of 0.5 g. of this ke'tone, 100 mg. of p-toluenesulfonic acid, 3 ml. of ethyleneglycol and 100 ml. of benzene isrefluxed using a water separator for 24 hours. The reaction mixture is cooled and then 100 ml. of ethanol and 2 g. of potassium hydroxide are added. This mixture is refluxed for 6 hours, cooled, diluted with water and the corresponding ethylene ketal is isolated by extraction with ethyl acetate. A solution of 0.1 moles of the ketal in ml. of dime'thylformamide containing 0.] moles of triphenylphosphine is reacted with 0.] moles of carbon tetrabromide at room temperature for 18 hours. The mixture'is diluted with of formula XVII and there are obtained the substituted tricarbocyc'lic ketones (XVII) which are useful in the water and extracted with ether. The ether extracts are combined, washed with water, dried and evaporated. The residue is chromatographed on 400 of alumina eluting with hexane-benzene and benzene to give the ethylene ketal of Y-brorno-3-methylpentan4-one.

EXAMPLE 9 A mixture of 10 g. of l-chloropentan-4-one, ml. of ether and l g. of lithium aluminum hydride is allowed to stand at 20C for 20 hours. The reaction mixture is diluted with water and separated. The organic phase is washed with water, dried and evaporated to give l-chloropentan-4-ol which is purified by distillation. Two ml. of dihydropyran is added to a solution of l g. of l-chloropentan-4-ol in 15 ml. of benzene. About I ml. is removed by distillation to remove moisture and 0.4 g of p-toluenesulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for 4 days and is then washed with aqueous sodium carbonate solution and water, dried and evaporated to yield 4-(tetrahydropyran-2'-yloxy)-lchloropentane which is subjected to the procedure described in Example 2 to give the phosphonate (XX).

ca -in-cn -cnrcm-l wn Q-o-oa- 0 cn (xxx EXAMPLE in which R is benzoyl'oxy) in 60 ml. ofdry monoglyme while maintaining the temperature of about 78. The

reaction mixture is allowed to warm to room temperature and then left to stand at room temperature for about 2 hours. The reaction mixture is diluted with water and then extracted with ether. The ether extracts are combined, washed, dried over magnesium sulfate and evaporated under reduced pressure to afford the a,l3-unsaturated tricarbocyclic ketone XXII (R is methyl; AC is benzoyl) which can be purified further by chromatography on alumina.

(XXII) The'tricarbocyclic ketone (XXII) is a useful intermediate for the synthesis of l9-nor steroids using the pro cedure of US. Pat. Nos. 3,050,550, 3,019,252 or 3,150,152.

The phosphonate used in the process of this example can be prepared according to the following procedure.

A mixture of 10 g. of l-bromopentan-4-one, 100 ml. of carbontetrachloride and 5 g. of phosphorus penta chloride is refluxed for 10 hours. The reaction mixture is then cooled, washed with dilute sodium carbonate and water, dried over magnesium sulfate and evaporated to give l-bromo-4-chloropent-3-ene which is purified by distillation and converted into the phosphonate by the procedure described in Example 2.

EXAMPLE l l To a suspension of 4g. of diethyl 4,4-dimethoxybutylphosphonate in 50 ml. of dry monoglyme at about under nitrogen, there is added one equivalent of phenyl lithium in hexane with stirring. After about 5 minutes there is added 1.0 equivalent of the bicyclic enol lactone Vll (R is ethyl; R is in which R is benzoyloxy) in 50 ml. of dry monoglyme while maintaining the temperature at about 70. The reaction or mixture is allowed to warm to room temperature and then allowed to stand at room temperature for 3.5 hours. The reaction mixture is then diluted with water and extracted with ether. The ether extracts are combined, washed, dried over magnesium sulfate and evaporated under reduced pressure' The residue is chromatographed on silica gel to afford the a,B-unsaturated bicarbocyclic ketone XXIII (R is ethyl; Ac is benzoyl).

A mixture of l g. of the above bicarbocyclic ketone, 25 ml. of dioxane and 1 ml. of 5 percent aqueous HCI is boiled l5 minutes. The reaction mixture is allowed to cool, poured into water and the resulting mixture separated. The organic phase is evaporated to dryness to furnish the corresponding aldehyde which is taken up in 20 ml. of acetone, cooled .to 0C and a slight molar excess of Jones reagent (prepared by mixing 26 g of chromium trioxide with 23 ml. of concentrated sulfuric acid and diluting with water to ml.). Upon completion of the oxidation as followed by thin layer chromatography, the reaction mixture is diluted with water and then extracted with ethyl acetate. The ethyl acetate extracts are combined, washed with water, dried and evaporated under reduced pressure to afford the acid (XXIV) (R is ethyl; Ac is benzoyl) which is a valuable intermediate for the synthesis of known 19- nor-A and A -steroids useful as therapeutic agents using the procedure of, for example, Belgium Pat. No. 629,251 (1963); French Pat. No. 1,465,400 (1965) or Velluz et al., ibid.

OAo 0A0 0 R4 O OCH;

CH-OGH: H: CO\0H/ H} C CH2 (XXIII) (XXIV) benzene is added and the mixture stirred overnight followed by refluxing for two hours. The reaction mixture is cooled, washed with water and purified by vacuum distillation to give B,B-dimethoxyethylmalonic, acid diethyl ester. A mixture of g. of this ester in 100 ml. of ethanol containing 5 g. of sodium hydroxide is heated under reflux until evolution of carbon dioxide ceases. The reaction mixture is then saturated with carbon dioxide and evaporated to dryness under vacuum. Theresidue is suspended'in 50 ml. of drydimethylformamide to which is added a large excess-of methyl iodide. The reaction mixtureis stirred at room temperature for about 2-4 hours and then poured into water. The resulting mixture is extracted with ether and the ether extractscombined, washed with water and evaporated to give 4,4-dimethoxybutyric acidmethyl ester which is purified by distillation. A mixture of 4 g. of this methyl ester, 50 ml. of dry'te trahydrofuran and 1.1

equivalents'of lithium aluminum hydride is refluxed overnight. The reaction mixture is allowed to cool and then filtered with water. This mixture is extracted with ether and the ether extracts are combined, washed, dried and evaporated to dryness to afford 4,4- dimethoxybutanol [(CH O) CHCH --CH CH- 2 l- A solution of 0.1 moles of 4,4-dirnethoxybutanol in 50 ml. of dimethylformamide containing 0.1 moles of triphenylphosphine is allowed to react for 18 hours with 0.1 moles of carbon tetrabromide. The mixture is diluted with water and extracted with ether. The ether extracts are combined, washed with water, dried and evaporated to a crude product which is purified by distillation to yield 4,4-dimethoxybutylbromide. This bromide is then converted into the diethyl phosphonate using the procedure described in Example 2.

EXAMPLE 12 A. To a suspension of 2 g. of the phosphonate (XXV; R is methyl) in 50 ml. of diglyme at 78' under nitrogen, there is added one equivalent of n-butyl lithium in hexane with stirring. After about 5 minutes, there is added one equivalent of the bicyclic enol lactone (V11; R is methyl, R is ethylenedioxy) in 50 ml. of diglyme while maintaining the temperature at about 78. The temperature is allowed to rise toabout -20 and the mixture'to then stand for about 2 hours. There is then added m1. of hexamethylphosphoramide and the mixture heated at reflux for 12 hours. The mixture is allowed to cool and then is diluted with water followed by extraction with ether. The ether extracts are washed, dried and evaporated under reduced pressure to give the bicarbocyclic ketone (XXVI; R is methyl; R is ethylenedioxy) which is a useful intermediate for preparing enol lactones of formula 1.

' tained.

, o 00011 on, v

xxvr 1n the above formula, R, R and R are as defined hereinabove.

Phosphonates of formula XXV can be prepared as followsz B. To a solution of 5.5 g. of sodium hydride in 200 ml. of dry tetrahydrofuran under nitrogen, there is added one equivalent of dry dimethylphosphite. The mixture is cooled in an ice bath and stirred at 0 for 1.5 hours. One equivalent of 4,4-dimethoxybutylbromide in 60 ml. of dry tetrahydrofuran is added and the mixture stirred for 15 minutes at 0 and allowed to stand 1'6 hours at room temperature. The mixture is then heated under reflux for three hours, cooled and filtered- The filtrate is concentrated under reduced pressure and the concentrate taken up in ether. This mixture is shaken with saturated aqueous sodium chloride and then separated. The organic layer is evaporated under reduced pressure to give dimethyl 4,4-dimethoxybutylphosphonate.

By using other phosphites, e.g., diethylphosphite,-diphenylphosphite, dibenzylphosphite, and the like, in place of dimethylphosphite in the above procedure, the corresponding disubstituted phosphonates are ob- C. A mixture of l g. of dimethyl 4,4-dimethoxybutylphosphonate, 25 ml. of dioxane and 1 ml. of 5 percent aqueous HCl is heated at reflux for 15minutes. The mixture is allowed to cool and then poured into water and separated. The organic phase is evaporated to dryness to furnish the corresponding aldehyde. The aldehyde is stirred with four equivalents of argentic oxide in tetrahydrofuranzwater (9:1) at about 25 for 14 hours Extraction with etherzethyl acetate followed by drying over magnesium sulfate and evaporation under reduced pressure gives the phosphonate (XXV; R is methyl).

' 1 EXAMPLE l3 Diethyl methylphosphonate (1.94 g.) suspended in 50 ml. of dry tetrahydrofuran is treated with 1.1 equivalents of butyl lithium in hexane under nitrogen at about 78. After 10 minutes, one equivalent of benzalphthalide in .10 ml. of tetrahydrofuran is added while maintaining the temperature at about 78. The reaction mixture is allowed to warm to room temperature and then left to stand at room temperature for three hours. The reaction mixture is diluted with water and then extracted with ether. The ether extracts are combined, washed with water, dried and the solvent removed under vacuum. The residue is chromatographed on silica eluting with methylene, chloridezhexane (4:1) to afford 3-benzylind-2-en-Lone and a small amount of starting material.

By subjecting the ketone (XXl) to acid hydrolysis, e.g., dilute HCl at room temperature,.the corresponding alcohol (XXI) is obtained which is oxidized using chromium trioxide in pyridine at room temperature to the carbonyl (XXl") which is converted into estrogens according to U.S. Pat. No. 3,150,152.

The process of Example 3 is repeated with the exception that the phosphonate (XXX) (R is ethyl) is used in place of dimethyl methylphosphonate and there is obtained the substituted bicarbocyclic ketone (XXXI) (R is methyl; Ac is benzoyl).

The novel bicarbocyclic ketone (XXXI) is useful for the preparation of theknown tricarbocyclic ketones (XXll) which can'be used to prepare l9-nor steroids.

Thus, hydrogenation of the bicarbocyclic ketone using, for example, percent palladium-on-charcoal in ethanol followed by deketalization under mild condition such as 1 percent sulfuric acid in dioxane with refulxing for one hour furnishes the intermediate (XXXll) which can be cyclized using, e.g., a base as described by, e.g., Velluz et al., ibid., US. Pat. Nos. 3,102,145 and 3,150,152, or French Pat. No. 1,480,247, to furnish the tricarbocyclic ketone XXII (Ac is hydrogen).

('11 (EU, ii-c 2:0

on, cu,

xxxu) The phosphonate (XXX) can be prepared using the following procedure.

A mixture of 0.5 moles of 1,3-dithiane and 300 ml. of tetrahydrofuran cooled to --30 is treated with 0.5 molar equivalents of 1.5 molar n-butyl lithium in hexane undernitrogen and stirred for hours at Then 0.5 moles of the tetrahydropyranyl ether of 3- bromopropanol in 200 ml. of tetrahydrofuran is added slowly with stirring at 5 and then left for 14 hours at 0 under nitrogen. The resulting mixture is cooled to and treated with an additional 0.5 molar equivalents of 1.5 molar n-butyl lithium in hexane. After 1.5 hours, 0.5 moles of 4-chloro-l-bromopent-3-ene in 200 ml. of tetrahydrofuran is added. The reaction mixture is left standing for 18 hours at 0 and then allowed to warm to room temperature for 4 hours. Water is added and the resulting mixture extracted with ether. The ether extracts are combined, washed with water, dried and concentrated. The resulting dialkylated thiane (XXXIII) is dissolved in methanol and stirred for 2 hours with 20 ml. of 1 percent oxalic acid solution. The reaction mixture is poured into water containing an excess of sodium carbonate solution and then extracted with ether to afford the corresponding free hydroxy compound. The free hydroxy compound is dissolved in dry ethylene glycol containing 0.5 g. of mercuric chloride. This reaction mixture is allowed to stand overnight and then heated to 60 for 5 hours. After cooling, water is added and the ketal (XXXIV) isolated by extraction with ether. A mixture of 2 g. of the ketal and 30 ml. of methylene chloride. The mixture is left standing at 0 for 18 hours and then allowed to warm to room temperature. The mixture is then diluted with water and the resulting tosylate isolated by extraction with methylene chloride and purified by chromatography on deactivated alumina. This tosylate (0.5 g.) in 25 ml. of acetone is refluxed for 24 hours with 0.5 g. of sodium iodide. After cooling, the reaction mixture is diluted with water and extractedwith ether. The resulting crude iodide is treated with sodium hydride and diethyl phosphite as described in Example 2 to furnish the phosphonate (XXX) (R is ethyl).

Alternatively, the tosylate can be reacted with sodium hydride and diethyl phosphite using the procedure of Example 2 to obtain the phosphonate.

By repeating the preparation using other phosphites, e.g., dibutyl phosphite, dicyclohexyl phosphite, di-

methyl phosphite or diphenyl phosphite in place of diethyl phosphite, the corresponding phosphonates are obtained.

(XXXIII) EXAMPLE 15 The process of Example 2 is repeated using as the phosphonate reagent, the phosphonate of formula XXXV (R is ethyl) and there is obtained the tricarbocyclic ketone (XXXVl) (AC is benzoyl) which can be converted into l9-nor steroids or androstane steroids by. methods disclosed in the Journal of American Chemical Society, 82, No. 21, 5464 (1967); for example, by hydrogenolysis e.g., using palladium or Raney nickel followed by aqueous base treatment of the intermediate carbinolamide e.g., by refluxing with oxygen free methanolic sodium methoxide and then with 3 percent aqueous sodium hydroxide.

O CHr-CIIg-i (O R):

CH H;

(XXXV) (XXXVI) The phosphonate (XXXV) can be obtained according to the following outlined procedure.

COgCH; COCl COCHN:

CHr-CHg-Bf cam-en. I

(XXKV) Ten grams of the isoxazole (1 is heated at refluxwith 200 ml. of 1 percent sodium hydroxide in methanol for 5 hours. The reaction. mixture is then acidified to pH 3 with HCl and the acidified mixture is then concentrated to a small volume under reduced pressure. Water is added and the acid isolated by extraction with ethyl acetate. The crude acid (9 g.) is taken up in methanol and treated with one equivalent of sodium meth-' oxide. The-alcohol is evaporated and the residue dried under reduced pressure. The residue is then suspended in dry benzene and treated at 0C with an excess of oxa lyl chloride. Ater the evolution of gas ceases, the reaction mixture is allowed to warm to room temperature and the excess of oxalyl chloride removed by evaporation of the solvent medium to dryness.xThe resulting acid chloride (2) is taken up in benzene and treated with an excess of ethereal diazomethane. After the formation of the diazoketone is complete, the ether is removed and the resulting diazoketone heated under reflux in octane-Z-ol until nitrogen evolution ceases. The crude product is purified by distillation and reduced with an excess of lithium aluminum hydride in 200 ml. of tetrahydrofuran under reflux. The reaction mixture is decomposed by cautious addition of ethyl acetate and the inorganic salts precipitated by the addition of concentrated sodium sulfate solution. The solution is then filtered and evaporated to yield the alcohol (5) which is purified by distillation. The alcohol (5) is then treated with phosphorus tribromide in benzene to give the bromide (6) which is converted into the phosphonate (XXXV) by the procedure described in Example EXAM PLE l 6 R RI O O CHI-i (0 B)! a H n H C CH Cfig Cm (xxxvn') (XXXVIII) The process of Example 3 is repeated with the exception that dimethyl methylphosphonate is replaced with an equivalent amount of the phosphonate (XXXVll) (R is ethyl; R is hydrogen: R is methyl) and the corresponding substituted (1, B-unsaturate'd bicarbocyclic ketones XXXVIll are obtained.

The bicarbocyclic ketones of formula XXXVllI are excellent intermediates for the production of valuable 7-methyl steroids using the procedures described in Example 4. I

The phosphonates of formula XXXVll can be prepared according to the following outlined procedure wherein R R and X are as defined hereinabove.

(XXXVII) A solution of 0.6 moles of the aldehyde (7) and 0.5 moles of methyl a-bromopropionate in ml. of dry benzene is added dropwise to 0.6 moles of zinc dust. After 15 ml. of the solution is added, the mixture is heated to initiate the reaction. The remaining portion of the solution is then added during one hour. The resulting mixture is cooled, washed with water, dried and then refluxed with 0.2 g. of p-toluenesulfonic acid for five hours. After cooling, the reaction mixture is washed with dilute sodium bicarbonate solution and water and then dried and purified by distillation to give (8). One gram of 8 in 25 ml. of ethanol is hydrogenated with 0.1 g. of 5 percent palladium-on-carbon catalyst.

until 1 molar equivalent of gas is taken up. The catalyst. is filtered off and solvent evaporated to give 2-methyl- 3-(substituted phenyl)propionic acid methyl ester. One

gram of this ester in l ml. of tetrahydrofuran is reduced with 2 g. of lithium aluminum hydride until thin layer chromatography indicates the absence of starting ester. The reaction mixture is cooled, treated cautiously with an excess of ethyl acetate followed by saturated sodium sulfate solution. The organic layer is decanted off, dried with sodium sulfate and evaporated to give the alcohol (9) which is converted into the corresponding halide or tosylate (10) by procedures described herein (see Examples 4, 8 and 14). The halide or tosylate 10) is then converted into the phosphonate (XXXVIl) using the procedure described in Example 2.

EXAMPLE 17 The process of Example 3 for the preparation of the benzoyl bicyclic enol lactone (Vll) is repeated with the exception that acetyl chloride and trimethylacetyl chloride is used in place of benzoyl chloride and there is obtained the corresponding carboxylic esters of Vll, that is, the acetate and trimethylacetate.

EXAMPLE 18 To 0.25 ml. of diethyl 4-cycloethylenedioxypentylphosphonate in 8 ml. of tetrahydrofuran at 78 under argon is added 1.6 molar equivalents of butyl lithium in 0.40 ml. of hexane with stirring. After 15 minutes at 78, 014g. of the enol lactone (l'; R is methyl) in 8 ml. of cold tetrahydrofuran is added. The solution is stirred for 0.5 hours at '78 and then set aside at room temperature for six hours. The solvent is concentrated under vacuum and solution of 2 g. of potassium hydroxide, 2 ml. of water and 25 ml. of methanol is added and the mixture refluxed 1.5 hours under nitrogen. Concentration under vacuum, dilution with saturated aqueous sodium chloride and isolation with ether yields ll (R is methyl).

To 0.18 g. of ll is added 4 ml. of acetic acid and 0.5 ml. of water and the solution heated to 80 for 1.5 hours. The solution is concentrated under vacuum and isolation with ether yields lll' (Ris methyl) with the tbutyl group (R) intact. The a,,B-unsaturated diketone (lll') in 10 ml. of 0.2 percent triethylamine in 95 per cent aqueous ethanol is hydrogenated at at room temperature and pressure over percent paladium-oncharcoal until 1 equivalent of hydrogen is absorbed (about 15 minutes). The mixture is filtered and the filtrate evaporated to yield the saturated dione (IV').

A mixture of 20 mg. of the dione (IV), ml. of methanol, 1 ml. of water and 0.5 g. of potassium hydroxide is heated under reflux for 2.5 horus under nitrogen. The mixture is allowed to cool and then evaporated under vacuum. The residue is taken up in ether,

washed, dried over sodium sulfate, and evaporated to' dryness to yield the t-butyl ether of l9-nortestosterone (V'; R is methyl).

A mixture of mg. of the dione UV), 5 ml. of

methanol, 1 ml. of-water and 2 ml. of 37 percent hydrochloric acid is refluxed under nitrogen for 3 hours. The solvent is removed under vacuum and isolation with ether gave l9-nortestosterone (Vl; R is methyl).

The following procedure is used for preparing the enol lactones of formula I wherein R and R are as defined therein.

(xxx

A suspension of 0.5 g. of the hydroxy acid (XXX; R is methyl) in 40 ml. of methylene dichloride is cooled to and then 40 ml.- of isobutylene and 0.6 ml. of 93 percent sulfuric acid areadded. This reaction mixture is shaken for 17 hours in a pressure vessel. The vessel is then recooled to 70, opened and the solution poured into aqueous sodium bicarbonate with stirring. lsolation with methylene dichloride gave the ester xxx' A mixture of 0.08 g. of the ester (XXXl; R is methyl), 50 ml. of ethanol, 10 ml. of water and 5 g. of potassium hydroxide is heated under reflux for 2.5 hours. Solvent is removed, water added, and extraction with ether. The aqueous phase is adjusted to pH 2 and the acid (XXXll') isolated with ether.

A mixture of 0.24 g. of the acid (XXXII'; R is methyl, 0.6 g. of sodium acetate and 10 ml. of acetic anhydride is refluxed under nitrogen for 4 hours The reaction mixtureis evaporated under vacuum and the residue treated with ether and aqueous sodium bicarbonate. lsolation with ether gave the tricyclic enol lactone (I'; R is methyl).

The hydroxy acids (XXX') can be prepared using the procedure of Valluz et al., ibid. or French Pat. No.

' 1,465,400 (1965) by the reaction of the lower alkyl ester of 5-keto-6-heptenoic acid with a 2- loweralkylcyclopentane-l,3-dione (prepared by the method of US. Pat. No. 3,318,922) in the presence of base, e.g., triethylamine followed by cyclization with acid hydrolysis, reduction and hydrogenation.

COzH

COiH

(XXX?) As an alternate method, the hydroxy acid can beprepared by reacting a'bicyclic enol lactone of formula V1] with diethyl 4, 4-dimethoxybutylphosphonate anion followed by hydrolysis, oxidation of the aldehyde to'the acid and then hydrogenation with palladium-oncharcoal. The bicyclic enol lactonestVll) can'be obtained according to the method of French iPat. No. l,496,8l7 (1966) :using a 2-lower.alkylcyclopentane- 1,3-dione and ethylacrylate to yield ethyl B-( l --lower alkyl-2', 5-dioxocyclopen tyl)propionate. The 2-oxo group is then modifiedfif desired, using conventional procedures such as forming the correspondingethylenedioxy or forming the corresponding hydroxyl by reduction andthen esterification or etherification and thereafter-hydrolysis and cyclization is performed. The tricyclic enol lactones of formula I can be similarly prepared using the method of Netherlands Pat. No. 6,414,702 (1965).

EXAMPLE 19 ./C$ CH I =CHP(OB):

(VII) In the above formulas, R, R and R are as defined hereinabove and k is hydrogen or one of the following groups:

OCH

or CHz-CHr-COOH A. To a solution of 4 g. of diethyl 4-cycloethylenedioxypentylphosph'onate in 50 ml. of tetrahydrofuran undernitrogen at 78, there is added one equivalent of'n-butyl lithium in hexane with stirring. After about fiveminutes at 78, one equivalent of the enol lactone (VII; R is methyl, R is ethylenedioxyl) in ml. of tetrahydrofuran is added and the reaction mixture allowed to rise to about 2(}. After about 1 hour, the

mixture is diluted with water followed by extraction with ether. The ether extracts are washed, dried and evaporated'under reduced pressure to yield the intermediate phosphonate (XXXIX; R is ethyl, R is methyl, R is ethylenedioxy, R? is 3cycloethylenedioxybutyl).

B. A'solution of the intermediate phosphonate ob.- tained in Part A in ml. of ethanol and 1 equivalent of sodium ethoxide is heated at reflux for about six hours and then allowed to cool to about room temperature followed by extraction with ether. The ether extracts are washed, dried and evaporated under reduced pressure to yield the bicarbocyclic ketone (XL; R is methyl, R is ethylenedioxy, R is 3-cycloethylenedioxybutyl) which can be further purified by chromatogra- In the above formulas, R is as defined above and alkyl is lower alkyl.

EXAMPLE 20 v The process of Part A of Example 19 is repeated using the phosphonates (IX) and (XXXVlI) in place of diethyl 4-cycloethylenedioxypentylphosphonate to yield the intermediate phosphonates (XXXlX) wherein R is RID-Q LB-R EXAMPLE 2l our) in the above formulas, R, R and R are as defined hereinabove and R is hydrogen or methyl or one of the following groups:

in which OR is a labile ether group convertible into the corresponding hydroxy such as tetrahydrofuran-2- yloxy, tetrahydropyran-Z'-yloxy, t-butoxy, methoxy, and the like.

The process of Part A of Example 19 is repeated using the tricyclic enol lactone (l; R is methyl, R is ethylenedioxy) in place of the bicyclic enol lactone (VII) to yield the intermediate phosphonate (XLI', R is ethyl, R is methyl, R is ethylenedioxy, R is 3-cycloeu ao P-cm-wmn/ j-CH.

OCH.

thylenedioxybutyl) which is subjected to the procedure of Part B of Example 19 to the tricarbocyclic ketone (XLII; R is methyl, R is ethylenedioxy, R is 3-cycloethylenedioxybutyl).

The other intermediate phosphonates and tricarbocyclic ketones of formulas XL] and XLII, respectively, are also prepared by the foregoiong procedure using the following phosphonates:

o o Re l -ca om; (Emi -err.

err, o 0 noni -cm-cnr EXAMPLE 22 To a suspension of 2 g. of dimethyl methylphosphonate in 50 ml. of dry tetrahydrofuran at -78 under nitrogen, there is added one equivalent of n-butyl lithium in hexane with stirring. After about'5 minutes, there is added one equivalent of bicyclic enol lactone (Vll; R is methyl, R is ethylenedioxy) in 50 ml. of dry tetrahydrofuran while maintaining the temperature at about 78. The reaction mixture is allowed to warm to room temperature and to stand at room temperature for 24 hours. The reaction mixture is diluted with water and then extracted with ether. The ether extracts are combined, washed, dried and evaporated under reduced and ' pressure to give the bicarbocyclic ketone (Vlll: R is methyl, R is ethylenedioxy).

EXAMPLE 23 To a mixture of 2 g. of the phosphonate of formula [X (R is ethyl, R is hydrogen, R is methyl) in 50 ml, of dry tetrahydrofuran at 78 under nitrogen, there is added one equivalent of n-butyl lithium in hexane with stirring. After about 5 minutes, there is added one equivalent of the bicyclic enol 'lactone (Vll; R is methyl, R is ethylenedioxy) in 50 ml, of dry tetrahydrofuran. The reaction mixture is allowed to warm to room temperature. To the reaction mixture is added I00 ml. of ethanol and 2 g. of sodium ethoxide. The

mixture is then. refluxed for five hours. After cooling,

the mixture is diluted with water and then extracted with ether. The ether extracts are washed, dried and evaporated under reduced pressure to give the bicarbocyclic ketone (X) in which R is hydrogen, R is methyl,

R is methyl and R is ethylenedioxy.

EXAMPLE 24 To a mixture of 3 g. of the phosphonate (XXXVII: R is methoxy, R methyl, R is ethyl) in 75 ml. dry diglyme at 78" under nitrogen, there is added one equivalent of n-butyl lithium in hexane with stirring. After about 5 minutes, there is added one equivalent of the bicyclic enol lactone VII: R is ethyl, R is ethylenedioxy) in 50 ml. of dry diglyme. The reaction mixture is allowed to rise to room temperature. To the reaction mixture is added 40 ml. of hexamethylphosphoramide (hexamethylphosphorictriamide) and the mixture heated at reflux for 18 hours. After cooling, the mixture is diluted with water and extracted with ether. The ether extracts are washed, dried over magnesium sulfate, and evaporated under reduced pressure to yield of the biocarbocyclic ketone (XXXVIII) in which R is methoxy, R is methyl, R is ethyl and R is ethylenedioxy.

EXAMPLE 25 The process of Example 5 is repeated with the exception that after the reaction mixture is allowed to warm to room temperature, there is added 100 ml. of metha-- nol containing 1 g. of potassium hydroxide and the mixture heated at reflux for hours to give 173- hydroxyandrost-4-en-3-one.

EXAMPLE 26 The'phosphonate (XVII; R is ethyl) is reacted. with the tricyclic enol lactone (I'; R is ethyl) using the method of Example 24 to yield the tricarbocyclic ketone (XVIII) in which R is ethyl and R is wherein R is t-butoxy.

EXAMPLE 27 The process of Example ll is repeated with the exception that the enol lactone is an enol lactone of formula VII wherein R is methyl and R" is ethylenedioxy and after the reaction mixture is allowed to warm to room temperature there is added 100 ml.'of methanol and 1.5 g. of sodium hydroxide and the mixture-refluxed for seven hours to yield a bicarbocyclic ketone of formula XL in which R is methyl, R is ethylenedioxy and R is 3,3-dimethoxypropyl.

The phosphonate (XXX; R is ethyl) and enol lactone (VlI;-R is ethyl, R" is ethylenedioxy) are reacted using the procedure of Example 28 to yield the bicarbocyclic ketone (XL) in which R is ethyl, R is ethylenedioxy and R is EXAMPLE 2s The phosphonate (XXXV; R is ethyl) and enol lactone (I; R is ethylenedioxy) are reacted using the procedure of Example 23 to afford the corresponding tricarbocyclic ketone of the following formula;

Example 19 is repeated using an enol lactone (VII) in which R is methyl and R is in which R is t-butoxy to afford the corresponding intermediate phosphonate (XXXIX) and bicarbocyclic compounds (XL) in which R and R" are as defined therein, R is methyl and R is in which R is t-butoxy. I

Similarly, Example2O is repeated using the t-bu tyl ether of enol lactone VII as the starting material.

Two gramsof the unsaturated bicarbocyclic ketone (LX; R is methyl, R is ethylenedioxy) in 25 ml. of.0.2 percent triethylamine and 100 ml. of percent aque ous ethanol is hydrogenated at room temperature and room pressure over 5 percent palladium-on-charcoal until one equivalent of hydrogen is absorbed. The mixture is filtered and the filtrateev'aporated to yield the corresponding saturated bicarbocyclic ketone (LXI).

A mixture of one gram of the saturated bicarbocyclic ketone (LXI), l00 ml. of methanol, 10 ml. of water and 20 ml, of 37 percent hydrochloric acid is heated at reflux for 2 hours under nitrogen. The solvent is removed under reduced pressure and isolation with ether affords the unsaturated tricarbocyclic diketone (LXII; R is oxo) which is hydrogenated using the procedure described above to yield the corresponding saturated tircarbocyclic diketone which is subjected to oxidation using chromium trioxide in pyridine or Jones reagent to yield saturated triketone (LXll l.).

Other compounds of formula LX (prepared as described in Example 19) can be used in the above procedure to obtain other useful intermediate of formula LXlll.

EXAMPLE 30 R 1) H CH1 EYE: H: CH H,

EXAMPLE 31 The unsaturated bicarbocyclic ketone (LXVlyR is methyl, R is methylenedioxy) is hydrogenated over palladium-on-charcoal using the procedure described above to give the corresponding saturated bicarbocyclic ketone which is cyclized using acid by the procedures described above to yield the tricarbocyclic ketone (LXVll; R" is methyl, R is oxo) which can be converted into l9-nor steroids by methods disclosed in Journal of the American Chemical Society 82, No. 21,

EXAMPLE 32 The bicarbocyclic ketone (LXVlll; R is ethylenedioxy) is subjected to the procedure of Example 30 to yield the tricarbocyclic ketone (LXlX; R is oxo).

' Similarly, the biocarbocyclic ketone (LXX; R is ethylenedi'oxy) can be converted into the tricarbocyclic ketone (LXIX, R is oxo).

r C a (LIX) EXAMPLE 33 (LXXIII) The bicarbocyclic ketone (LXXI; R is ethylenedioxy) is treated withacid using the procedure of US. Pat. No. 3,050,550 to give the triketone (LXXlI; R is oxo) which is hydrogenated over palladium-oncharcoal and then cyclized using acid to the tricarbocyclic diketone (LXXlll).

The procedure of Example l2 is repeated with the exception that after the mixture is allowed to cool the mixture is adjusted to pH 4 and then the bicarbocyclic ketone (XXVI) is isolated as described therein.

The procedure of Example l9 is repeated using an enol lactone (VII; R is methyl, R is the group in which R is acetoxy) to yield the carbocyclic ketone (Xl) in which R is methyl, R is the group wherein R is hydroxy and R is as defined therein.

The term carbocyclic," as used herein, refers to saturated carbocyclics such as cyclohexyl, and the like,

, and unsaturated carbocyclics (i.e., mono-aryl) such as tolyl lithium and methyl potassium lithiur'n pyridide, with about an equal molar amount of a phosphonate selected from the group having the formulas:

- O O 1 l CH3L (OR) 2 and R cH i (OR) 2 wherein R is selected from the group consisting of lower alkyl having from one to six carbon atoms, cyclohexyl, phenyl, tolyl, trich'loro'phenyl and benzyl, and wherein R is a group having the formula:

O O Cl -CH CH y CH H -CH Z C 2 2 I C 2 Q I -CH --CH -CH-CH 7 or wherein OR is an acid labile ether group selected from the group consisting of tetrahydrofuran-2'-yloxy, tetrahydropyan-2-yloxy, t-butoxy and methoxy, thereby generating the corresponding carbanion; and

b. reacting in situ with said carbanion about an equal molar amount of anrenol lactone having the formula:

wherein R is methyl or ethyl and R is 0x0 or a lower alkylenedioxy having one to six carbon atoms thereof or the group 8 in which R is hydroxy, a carboxylic ester having less than 12 carbon atoms, or an acid labile ether selected from the group consisting of t-butoxy, tetrahydropyran- 2-yloxy, tetrahydro-furan-2-yloxy,-methoxy, ethoxy and methoxymethyleneoxy, thereby producing the corresponding a,B-unsaturated carbocyclic ketone.

2. The process of claim 1 wherein said phosphonate is a phosphonate of formula A and R is lower alkyl having one to six carbon atoms or monocyclic selected from the group consisting of cyclohexyl, phenyl, tolyl, and trichlorophenyl.

3. The process of claim 1 wherein said phosphonate is a phosphonate of formula B wherein R is methyl or one of the groups:

in which 0R is an acid labile ether group selected from the group consisting of tetrahydrofuran-Z'-yloxy, tetrahydropyran-Z '-yloxy, t-butoxy and methoxyv 4. The process of claim 3 wherein R is the'group;

and R is lower alkyl having from one to six carbon atoms or phenyl and R is the group in .which R is benzoyloxy or an acid labile ether selected from the group consisting of t-butoxy, tetrahydropyran-Z-yloxy, tetrahydrofuran-Z-yloxy, methoxy, ethoxy, and methoxymethyleneoxy.

5. The process of claim 1 wherein said phosphonate is selected from the group consisting 'of dimethyl methyl phosphonate, dimethyl ethyl phosphonate, diethyl methyl phosphonate, dicyclohexyl methyl phosphonate; diphenyl methyl phosphonate; butyl)methyl phosphonate; dibenzyl'methyl phosphonate; diethy'i methyl phosphonate; diethyl 4,4- ethylenedioxypent yl phosphonate; diethyl 4- chloropent-3-enylphosphonate; diethyl 4- (tetrahydropyran-Z '-yloxy )-pentylphosphonate; di-

ethyl and 4,4-ethylenedioxy-3methylpentyl phosphonate.

6. The process of claim 1 wherein the reaction mixture of step b) is allowed to rise to from C to room temperature and wherein a lower monohydric aliphatic alcohol selected from the group consisting of methanol, ethanol, isopropanol, and t-butanol is then added to the reaction mixture.

7. The process of claim 6 wherein a reagent selected from the group consisting of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, potassium methoxide, and sodium t-butoxide is added with the addition of said monohydric aliphatic alcohol and thereafter conducting said reaction at temperatures of from room temperature to reflux temperature.

8. The process of claim 3 wherein R is lower alkylenedioxy having one to six carbon atoms or the group 8 ina in which R in an acid labile ether selected from the group consisting of t-butoxy, tetrahydropyran-Z-yloxy, tetrahydrofuran-2-yloxy,' methoxy, ethoxy, and methoxymethyleneoxy; and R is a lower alkyl having one to six carbon atoms or phenyl and wherein the reaction of step b) is allowed to rise to a temperature of about from 0C to room temperature and thereafter conducting the reaction at a temperature of from room temperature to reflux temperature.

9. The process of claim 3 for preparing a, B-unsatu rated carbocyclic ketones wherein said a,B-unsaturated carbocyclic ketone has the formula:

10. The process of claim 9 wherein the temperature of the reaction mixture of step (b) is allowed to rise to from 0 to room temperature and a dipolar aprotic solvent selected from the group of hexamethylphosphoramide, dimethylformamide and dimethylacetamide is added to the reaction mixture and the reaction thereafter conducted at from room temperature to reflux temperature. 

1. A PROCESS FOR PREPARING A,B-UNSATURATED CARBOCYCLIC KETONES WHICH COMPRISES THE STEPS OF: A. REACTING AT TEMPERATURES IN THE RANGE OF FROM -150* TO -20:C UNDER ANHYDROUS CONDITIONS IN AN ORGANIC SOLVENT, INERT TO THE REACTION, A BASE SELECTED FROM THE GROUP CONSISTING OF ALKALI METAL HYDRIDES, ALKALI METAL AMIDES, AND ORGANO ALKALI METAL COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF N-BUTYL LITHIUM PHENYL LITHIUM. METHYL SODIUM, SODIUM ACETYLIDE, METHYL POTASIUM, METHYL LITHIUM, TOLYL LITHIUM AND METHYL POTASSIUM LITHIUM PYRIDIDE, WITH ABOUT AN EQUAL MOLAR AMOUNT OF A PHOTOSPHATE SELECTED FROM THE GROUP HAVING THE FORMULAS:
 2. The process of claim 1 wherein said phosphonate is a phosphonate of formula A and R is lower alkyl having one to six carbon atoms or monocyclic selected from the group consisting of cyclohexyl, phenyl, tolyl, and trichlorophenyl.
 3. The process of claim 1 wherein said phosphonate is a phosphonate of formula B wherein R1 is methyl or one of the groups:
 4. The process of claim 3 wherein R1 is the group;
 5. The process of claim 1 wherein said phosphonate is selected from the group consisting of dimethyl methyl phosphonate, dimethyl ethyl phosphonate, diethyl methyl phosphonate, dicyclohexyl methyl phosphonate; diphenyl methyl phosphonate; di-(n-butyl)methyl phosphonate; dibenzyl methyl phosphonate; diethyl methyl phosphonate; diethyl 4,4-ethylenedioxypentyl phosphonate; diethyl 4-chloropent-3-enylphosphonate; diethyl 4-(tetrahydropyran-2''-yloxy)-pentylphosphonate; diethyl and 4,4-ethylenedioxy-3-methylpentyl phosphonate.
 6. The process of claim 1 wherein the reaction mixture of step b) is allowed to rise to from 0*C to room temperature and wherein a lower monohydric aliphatic alcohol selected from the group consisting of methanol, ethanol, isopropanol, and t-butanol is then added to the reaction mixture.
 7. The process of claim 6 wherein a reagent selected from the group consisting of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, potassium methoxide, and sodium t-butoxide is added with the addition of said monohydric aliphatic alcohol and thereafter conducting said reaction at temperatures of from room temperature to reflux temperature.
 8. The process of claim 3 wherein R7 is lower alkylenedioxy having one to six carbon atoms or the group
 9. The process of claim 3 for preparing Alpha , Beta -unsaturated carbocyclic ketones wherein said Alpha , Beta -unsaturated carbocyclic ketone has the formula:
 10. The process of claim 9 wherein the temperature of the reaction mixture of step (b) is allowed to rise to from 0* to room temperature and a dipolar aprotic solvent selected from the group of hexamethylphosphoramide, dimethylformamide and dimethylacetamide is added to the reaction mixture and the reaction thereafter conducted at from room temperature to reflux temperature. 